Abstract Cannabis use is particularly prevalent and problematic amount youth. Compared with only one in eleven cannabis-exposed adults, one in six cannabis-exposed youth develops cannabis use disorder. Moreover, youth are more prone than adults to potentially lasting adverse effects of cannabis use, including cognitive impairment, altered brain development, poor educational outcome, and diminished life achievement. Despite this, relatively little work has focused on developing optimally efficacious cannabis use disorder treatments, particularly among youth. Current evidence-based treatments convey generally small to modest effect sizes, and novel approaches are critically needed. Among the most promising approaches are the over-the-counter antioxidant medication N-acetylcysteine (NAC) and the behavioral treatment contingency management (CM). Our team previously demonstrated superior NAC versus placebo (PBO) abstinence outcomes in youth with CUD who concurrently received CM. Further work is now needed to disentangle the effects of NAC and CM. It is possible that they are synergistic, with their combination being critical to maximizing abstinence outcomes. Alternatively, NAC may be efficacious independent of CM, but this has not been formally evaluated. In order to optimally translate NAC and CM findings to real-world clinical practice, their relative contributions to cessation outcomes must be formally evaluated. We propose a 12-week 2 x 2 factorial design trial of NAC and CM for CUD in youth (N=336). Participants will be randomized to double-blind NAC or PBO and to CM or no CM, yielding four equally-allocated treatment groups: NAC + CM, NAC + No CM, PBO + CM, and PBO + No CM. All participants will receive brief weekly cannabis cessation counseling and medication management. The primary efficacy outcome will be the proportion of negative urine cannabinoid tests during the 12-week active treatment, compared between groups. We will also serially assess cognitive task performance, examining changes in performance among participants who achieve abstinence versus those that do not. This proposed trial is the clear ?next step? in the assessment of NAC and CM as extremely promising youth CUD treatment modalities, and is positioned to inform researchers, clinicians, and the general public, addressing a critical need for optimization of youth CUD treatments.